16-53601339-A-C

Position:

• chr16-53601339-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_015272.5(RPGRIP1L):​c.*737T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,274 control chromosomes in the GnomAD database, including 12,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.38 (12812 hom., cov: 33)
  • Exomes 𝑓: 0.20 (2 hom.)
• Consequence: RPGRIP1L NM_015272.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.338

Genes affected

RPGRIP1L (HGNC:29168): (RPGRIP1 like) The protein encoded by this gene can localize to the basal body-centrosome complex or to primary cilia and centrosomes in ciliated cells. The encoded protein has been found to interact with nephrocystin-4. Defects in this gene are a cause of Joubert syndrome type 7 (JBTS7) and Meckel syndrome type 5 (MKS5). [provided by RefSeq, Jun 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 16-53601339-A-C is Benign according to our data. Variant chr16-53601339-A-C is described in ClinVar as [Benign]. Clinvar id is 319634.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGRIP1L	NM_015272.5	c.*737T>G		3_prime_UTR_variant	27/27	ENST00000647211.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGRIP1L	ENST00000647211.2	c.*737T>G		3_prime_UTR_variant	27/27		NM_015272.5

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57888 AN: 152032 Hom.: 12772 Cov.: 33

Gnomad AFR AF: 0.598

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.377

GnomAD4 exome AF: 0.198 AC: 25 AN: 126 Hom.: 2 Cov.: 0 AF XY: 0.183 AC XY: 15 AN XY: 82

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.381 AC: 57985 AN: 152148 Hom.: 12812 Cov.: 33 AF XY: 0.376 AC XY: 28004 AN XY: 74386

Gnomad4 AFR AF: 0.598

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.341

Gnomad4 EAS AF: 0.585

Gnomad4 SAS AF: 0.428

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.385

Alfa AF: 0.314 Hom.: 7152

Bravo AF: 0.395

Asia WGS AF: 0.509 AC: 1772 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Meckel syndrome, type 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.51
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3760008; hg19: chr16-53635251;